Therapeutic compositions of tetracycline group antibiotic and parahydroxybenzoic acid ester



THERAPEUTIC COMPOSITIONS F TETRA- CYCLINE GROUP ANTIBIOTIC AND PARA-HYDROXYBENZOIC ACID ESTER :No Drawing. Application April 15, 1954,Serial No. 423,516

6 Claims. Cl. 167-65 This invention relates to a therapeuticallyeffective composition consisting essentially of a mixture of anantibiotic, such as chlortetracycline, oxytetracycline, tetracycline,bromotetracycline, their salts or complexes or mixtures thereof, and atherapeutically effective amount, at least about 1% by weight, of analkyl or benzyl ester of para-hydroxybenzoic acid or a mixture of suchesters.

This application is a continuation-in-part of application Serial Number204,080 filed January 2, 1951, entitled Therapeutic Compositions and nowabandoned.

The composition may be used with a carrier, such as a sugar, in a trochefor oral use in the mouth, in tablets, in a dusting powder, and inlozenges, as well as in ointments, etc.

The esters of para-hydroxybenzoic acid have been frequently used aspreservatives for various types of products. Patent 1,627,342 toSabalitschka discloses the methyl ester :to the extent of 0.7% as apreservative for marmalade. A rather comprehensive summary of the use ofthe esters of para-hydroxybenzoic acid as preserve tives is found in theDrug and Cosmetic Industry 54; 408 (April 1944). The usual range as apreservative is from 0.05% to 0.2%.

We have found that, amazingly, therapeutically effective quantities ofthe esters, at least 1% by weight, exhibit remarkable characteristics inpreventing various undesirable side reactions which have previouslyoccurred with the administration of the tetracycline group antibiotics.We prefer to use from approximately 1 part of the parahydroxybenzoicacid ester to 8 parts of the antibiotic up to approximately equalportions of each, but not less than 1% by weight of thepara-hydroxybenzoate esters in the finished product as prepared foradministration. With low concentrations of antibiotic more of the estersthan other acid salts such as the hydrobromide, the sulfate, etc.

or alkali salts such as the sodium or calcium salts may be used, as wellas the neutral form of the tetracycline group antibiotic. r

It has been found that the tetracycline group antibiotics for examplechlortetracycline in troches, that is, chlortetracycline mixed with acarrier such as dextrose or other sugar, if used orally to inhibitbacterial growth in the oral cavity will sometimes cause the mouth tobecome inflamed, forming small white pustules, causing the membranes ofthe mouth to become thick, crack and extremely painful. At times themouth appearsto be showing symptoms of thrush. We have now'found that ifapproximately equal weight portions of an ester, or mixtures of esters,of para-hydroxybenzoic acid are mixed with the chlortetracycline, suchundesirable side reactions United States Patent 0 do not occur. Theproportions may vary widely depending upon the carriers used, and giveexcellent results,

Similar advantages are obtained in ointments and dental cones designedfor use in the mouth as well as preparations designed for use in otherbody cavities. The mixture of a tetracycline group antibiotic and anester of para-hydroxybenzoic acid in an ointment for use with infectionsof the skin prevents itching inflammations as a side reaction with fargreater etficacy than either component alone. The effect seems to betherapeutically synergistic in nature. The mixture has been particularlyeffective in a vaginal dusting powder, in suppositories, skin ointments,etc. The mixture alleviates or prevent-s diarrhea, with foamy stools,rectal itching, vaginal itching and bleeding, and certain itchingirritations of the skin, all of which symptoms are sometimes seen wherethe tetracycline group antibiotics are used without these esters. Theexact proportions may vary depending upon the antibiotic which is beingused, and its concentration in the carrier media.

The mixture is also effective internally where these antibiotics aretaken by mouth. chlortetracycline and oxytetracycline have from time totime caused undesirable side reactions in the gastro-intestinal tract.We find that if a lower alkyl ester or the benzyl ester ofparahydroxybenzoic acid, or a mixture of these, is administered withtheantibi-o'tic, it changes the effect of the antibiotic on theintestinal flora so that improved therapeutic effects are obtained. Weprefer the esters with from 1 to 7 carbons in the alcohol moiety.

. The use of the alkyl esters of para-hydroxybenzoic acid, particularlythe methyl and propyl esters, gives excellent results. Many variationsin such compositions are very useful; by way of example, but notlimitation, certain of these are shown below:

EXAMPLE 1 Chlortetracycline troches and then compressed into-1000troches on a standard pharmaceutical tableting machine; each containingapproximately 15 milligrams of chlortetracycline hydrochloride and 17milligrams of the esters (1.13% by weight of the para-hydroxybenzoateesters). The troches were administered to individuals with various typesof mouth infections, and were found to be very efiicacious. No cases ofthrush or sore mouth developed during the use of the troches.

EXAMPLE 2 Vaginal dusting powder talc was screened, mixed andbarrel-rolled for 10 minutes' 1.5 grams of lavender perfume were addedand the pow- A ders again barrel-rolled to insure uniform distributionof then-filled into suitable containers. The powder was used withindividual handshakers and with insutfiators and found to giveremarkable eflicient therapeutic action.

3 EXAMPLE 3 Oral capsules 1,444 grams of chlortetracyclinehydrochloride, 781 grams of methyl para-hydroxybenzoate and 195 grams ofpropyl para-hydroxybenzoate were screened and thoroughly mixed. Theblended powders were then filled into #1 shells. Each capsule containedapproximately of a gram of chlortetracycline hydrochloride. The capsuleswere found to be very effective, particularly for gastrointestinaldisorders. The capsules. contained 40.4% by weight of thepara-hydroxybenzoate esters.

EXAMPLE 4 Oral capsules grams of chlortetracycline hydrochloride and 5grams of methyl para-hydroxybenzoate were ground together until evenlydispersed. The composition was divided into hard shell gelatin capsulesfor administration. The capsules contained 33% by weight of thepara-hydroxybenzoate esters.

EXAMPLE 5 Grease base suppositories A mixture was prepared of 206 gramsof white wax, 341 grams of paraflin, 341 grams of anhydrous lanolin,1,383 grams of cetyl alcohol and 4,388 grams of mineral oil USP. Themixture was heated to C. and stirred until evenly blended. Thereto wasadded a powdered mixture containing a blend of 660 grams ofchlortetracycline hydrochloride, 62 grams of methyl para-hydroxybenzoateand 21 grams of propyl para-hydroxybenzoate The charge was homogenized,poured into torpedo shaped molds and chilled, each mold containingapproximately 0.25 gram of the chlortetracycline hydrochloride. Thesuppositories contained 1.12% by weight of the para-hydroxybenzoateesters.

EXAMPLE 6 Chlortetracycline vaginal ointment 17.25 grams of glycerylmonstearate, 34.50 grams USP lanolin, 51.75 grams of cerosin wax, 69grams of white petrolatum and 270 grams of mineral oil were mixed andmelted on a steam bath. 4.5 grams of chlortetracycline hydrochloride and4.5 grams of pulverized benzyl parahydroxybenzoate were then added tothe melt, the mixture homogenized, partially cooled, and poured intostandard ointment tubes. The finished product contained 1% each ofchlortetracycline hydrochloride and benzyl para-hydroxybenzoate.

EXAMPLE 7 Vaginal Oblets A granulation was prepared consisting ofchlortetraeycline hydrochloride and sucrose, mineral oil, methylpara'hydroxybenzoate and propyl para-hydroxybenzoate which Were blendedtogether with a small portion of acacia and yellow dye FDC No. 5 in suchproportions that when compressed in an Oblet punch, Oblets were obtainedcontaining:

Grams Chlortetracycline hydrochloride .2625 Blank granulation 1.9275Methyl p-hydroxybenzoate 0.0177 Propyl p-hydroxybenzoate 0.0048 Mineraloil 0.01085 If the granulation doesnot compress readily a mold lubricantmay be used to insure easier operation. A wetting agent may be added tothe formulation. The Oblets contained 1.01% by weight of thepara-hydroxybenzoate ester. 1 t t i i 4 EXAMPLE Oxytetracycline trochesChloreteracycline topical ointment A mixture was prepared of 83.7 gramsof white petrolatum and 10.0 grams of wool fat. The mixture was heatedto 55 C. and stirred until evenly blended. Thereto was added a powderedmixture containing a blend of 3.3 grams of chlortetracyclinehydrochloride, 2.4 grams of methyl para-hydroxybenzoate and 0.6 gram ofpropyl para-hydroxybenzoate. The charge was homogenized and poured intocontainers. The finished preparation contained 3.3% of chlortetracyclinehydrochloride and 3% of mixed parahydroxybenzoate esters by weight.

EXAMPLE 1O Tetracycline topical ointment A mixture was prepared as inthe preceding example, using 3.3 grams of tetracycline hydrochloride asthe antibiotic. ,The finished ointment was essentially the same inappearance and possessed similar characteristics.

EXAMPLE 11 Calcium chlortetracycline cream An ointment base was preparedmixing together 15 grams of glyceryl monostearate, 3 grams ofpolyethylene glycol monostearate, 5 grams of glycerin, 0.5 gram ofsodium sulfite and 0.7 gram of calcium acetate. This mixture washomogenized at 60 C. and cooled to room temperature. To this mixture wasadded 2.4 grams of methyl para-hydroxybenzoate, 0.6 gram of propylparahydroxybenzoate, 2 grams of iodochlorohydroxyquinoline and 1.1 gramof calcium chlortetracycline. The mixture was again stirred and theretowas added enough water to dilute to a finished weight of grams. Themixture was run through a colloid mill thereby producing a stabletopical ointment. This ointment makes an excellent topical preparationfor the treatment or prevention of skin infections.

As. will be seen, the various tetracycline group antibiotics may be usedin various forms. Greases, sugars, talc or other powders, etc. may beused as carriers or for dilution. Other therapeutically effective formsmay be used. For example, chlortetracycline hydrochloride currentlymeets the medical preference, and accordingly is used in preparing thecompositions set forth by example. Other acid salts of chlortetracyclineor the free neutral chlortetracycline or the salt of chlortetracyclinewith a base may be used.

Having set forth certain embodiments thereof, as our invention we claim:

1. A composition comprising a mixture of a tetracycline group antibioticfrom the group consisting of. chlortetracycline, oxytetracycline,tetracycline and bromotetracycline and their salts and complexes, and atleast one compound selected from the group consisting of the benzyl andthe lower alkyl esters of para-hydroxybenzoic acid containing from 1 to7 carbon atoms in the alcohol moiety, said esters of para-hydroxybenzoicacid being present in a therapeutically effective quantity greater thanabout 1% by weight of the total composition.

2. A therapeutic composition consisting essentially of a mixture of atetracycline group antibiotic and a therapeutically eifective quantitygreater than about 1% by weight of the total composition, of anester ofparahydroxybenzoic acid containing from 1 to 7 carbon atoms in thealcohol moiety.

3. A therapeutic composition consisting essentially of a mixture of atetracycline group antibiotic from the group consisting ofchlortetracycline, oxytetracycline, tetracycline and bromotetracych'neand their salts and complexes, a therapeutically effective quantitygreater than about 1% by weight, calculated on the weight of the totalcomposition, of a lower alkyl ester of para-hydroxybenzoic acidcontaining from 1 to 7 carbon atoms in the alcohol moiety, and an inertcarrier therefor.

4. A composition comprising a mixture of a tetracycline group antibioticfrom the group consisting of chlortetracycline, oxytetracycline,tetracycline and bromotetracycline and their salts and complexes, and atleast one compound selected from the group consisting of the benzyl andthe lower alkyl esters of para-hydroxybenzoic acid, containing from 1 to7 carbon atoms in the alcohol moiety, in which the weight ratio of theantibiotic is between about 8 parts and one part per part of the esterof para-hydroxybenzoic acid, said esters of para-hydroxybenzoic acidbeing present in a therapeutically effective quantity greater than about1% by weight of the total composition.

5. A therapeutic composition consisting essentially of 25 a mixture ofchlortetracycline hydrochloride and a therapeutically effectivequantity, not less than 12 /z% by weight of the quantity ofchlortetracycline hydrochloride, nor less than about 1% by weight,calculated on the weight of the total composition, of one of thecompounds selected from the group consisting of the benzyl and loweralkyl esters of para-hydroxybenzoic acid containing from 1 to 7 carbonatoms in the alcohol moiety.

6. Therapeutic capsules for oral administration comprising approximatelyMt of a gram of chlortetracycline hydrochloride and from /8 to A5 of agram of the esters of para-hydroxybenzoic' acid selected from the groupcon sisting of the benzyl and lower alkyl esters of para-hydroxybenzoicacid containing from 1 to 7 carbon atoms in the alcohol moiety.

References Cited in the file of this patent Metzger et al.:Antibacterial Action of Oral Aureomycin on the Contents of the Colon ofMan, Antibiotics and Chemotherapy, February 1952, pp. 91-102.

Ham's: Aureomycin and Chloramphenicol in Brucellosis, J. Am. Med. Assn.,vol. 142, 1950, pp. 161-165.

U. S. Dispensatory, 24th Ed., 1947, J. B. Lippincott Co., pp. 709 and710.

1. A COMPOSITION COMPRISING A MIXTURE OF A TETRACYCLINE GROUP ANTIBIOTICFROM THE GROUP CONSISTING OF CHLORTETTRACYCLINE, OXYTETRACYCLINE,TETRACYCLINE AND BROMOTETRACYCLINE AND THEIR SALTS AND COMPLEXES, AND ATLEAST ONE COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE BENZYL ANDTHE LOWER ALKYL ESTERS OF PARA-HYDROXYBENZOIC ACID CONTAINING FROM 1 TO7 CARBON ATOMS IN THE ALCOHOL MOIETY, SAID ESTERS OF PARA-HYDROXYBENZOICACID BEING PRESENT IN A THERAPEUTICALLY EFFECTIVE QUANTITY GREATER THANABOUT 1% BY WEIGHT OF THE TOTAL COMPOSITION.